tbuckley/cabot-search huggingface dataset:
HR121 targeting HR2 domain in S2 subunit of spike protein can serve as a broad-spectrum SARS-CoV-2 inhibitor via intranasal administration
Authors: Ying Lu, Fan Shen, Wen-Qiang He, An-Qi Li, Ming-Hua Li, Xiao-Li Feng, Yong-Tang Zheng, Wei Pang
Journal: Acta Pharmaceutica Sinica B (2023)

The continuously emerging SARS-CoV-2 variants pose a great challenge to the efficacy of current drugs, this necessitates the development of broad-spectrum antiviral drugs. In the previous study, we designed a recombinant protein, heptad repeat (HR) 121, as a variant-proof vaccine. Here, we found it can act as a fusion inhibitor and demonstrated broadly neutralizing activities against SARS-CoV-2 and its main variants. Structure analysis suggested that HR121 targets the HR2 domain in SARS-CoV-2 spike (S) 2 subunit to block virus-cell fusion. Functional experiments demonstrated that HR121 can bind HR2 at serological-pH and endosomal-pH, highlighting its inhibition capacity when SARS-CoV-2 enters via either cellular membrane fusion or endosomal route. Importantly, HR121 can effectively inhibit SARS-CoV-2 and Omicron variant pseudoviruses entering the cells, as well as block authentic SARS-CoV-2 and Omicron BA.2 replications in human pulmonary alveolar epithelial cells. After intranasal administration to Syrian golden hamsters, it can protect hamsters from SARS-CoV-2 and Omicron BA.2 infection. Together, our results suggest that HR121 is a potent drug candidate with broadly neutralizing activities against SARS-CoV-2 and its variants.
Avian influenza spillover into mammals
Authors: Priya Venkatesan
Journal: The Lancet Microbe (2023)

Since late 2020, a strain of highly pathogenic avian influenza virus A(H5N1) clade 2.3.4.4b has been circulating globally, leading to more than 50 million dead wild birds and culled poultry. Concerningly, the virus has also started to be detected in mammals. Cases of H5N1 infection have been previously noted in species such as minks in Spain and dolphins in South America. More recently (June 2022), an outbreak of A(H5N1) virus infections was reported among harbour and grey seals in New England, USA, that was concurrent with a large number of avian infections in the region.
Source-Specific Air Pollution Including Ultrafine Particles and Risk of Myocardial Infarction: A Nationwide Cohort Study from Denmark
Authors: Aslak Harbo Poulsen, Mette Sørensen, Ulla Arthur Hvidtfeldt, Jesper H. Christensen, Jørgen Brandt, Lise Marie Frohn, Matthias Ketzel, Christopher Andersen, Ole Raaschou-Nielsen
Journal: Environmental Health Perspectives (2023)

Background: Air pollution is negatively associated with cardiovascular health. Impediments to efficient regulation include lack of knowledge about which sources of air pollution contributes most to health burden and few studies on effects of the potentially more potent ultrafine particles (UFP). Objective: The authors aimed to investigate myocardial infarction (MI) morbidity and specific types and sources of air pollution. Methods: We identified all persons living in Denmark in the period 2005–2017, age >50 y and never diagnosed with MI. We quantified 5-y running time-weighted mean concentrations of air pollution at residencies, both total and apportioned to traffic and nontraffic sources. We evaluated particulate matter (PM) with aerodynamic diameter ≤2.5μm (PM2.5), <0.1μm (UFP), elemental carbon (EC), and nitrogen dioxide (NO2). We used Cox proportional hazards models, with adjustment for time-varying exposures, and personal and area-level demographic and socioeconomic covariates from high-quality administrative registers. Results: In this nationwide cohort of 1,964,702 persons (with 18 million person-years of follow-up and 71,285 cases of MI), UFP and PM2.5 were associated with increased risk of MI with hazard ratios (HRs) per interquartile range (IQR) of 1.040 [95% confidence interval (CI): 1.025, 1.055] and 1.053 (95% CI: 1.035, 1.071), respectively. HRs per IQR of UFP and PM2.5 from nontraffic sources were similar to the total (1.034 and 1.051), whereas HRs for UFP and PM2.5 from traffic sources were smaller (1.011 and 1.011). The HR for EC from traffic sources was 1.013 (95% CI: 1.003, 1.023). NO2 from nontraffic sources was associated with MI (HR=1.048; 95% CI: 1.034, 1.062) but not from traffic sources. In general, nontraffic sources contributed more to total air pollution levels than national traffic sources. Conclusions: PM2.5 and UFP from traffic and nontraffic sources were associated with increased risk of MI, with nontraffic sources being the dominant source of exposure and morbidity. https://doi.org/10.1289/EHP10556
CD71<sup>+</sup>erythroid cells suppress T-cell effector functions and predict immunotherapy outcomes in patients with virus-associated solid tumors
Authors: Najmeh Bozorgmehr, Isobel Okoye, Siavash Mashhouri, Julia Lu, Petya Koleva, John Walker, Shokrollah Elahi
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer. However, only a portion of patients respond to such treatments. Therefore, it remains a prevailing clinical need to identify factors associated with acquired resistance or lack of response to ICIs. We hypothesized that the immunosuppressive CD71 + erythroid cells (CECs) within the tumor and/or distant ‘out-of-field’ may impair antitumor response. Methods We studied 38 patients with cancer through a phase II clinical trial investigating the effects of oral valproate combined with avelumab (anti-programmed death-ligand 1 (PD-L1)) in virus-associated solid tumors (VASTs). We quantified the frequency/functionality of CECs in blood and biopsies of patients. Also, we established an animal model of melanoma (B16-F10) to investigate the possible effects of erythropoietin (EPO) treatment on anti-PD-L1 therapy. Results We found a substantial expansion of CECs in the blood of patients with VAST compared with healthy controls. We noted that the frequency of CECs in circulation was significantly higher at the baseline and throughout the study in non-responders versus responders to PD-L1 therapy. Moreover, we observed that CECs in a dose-dependent manner suppress effector functions of autologous T cells in vitro. The subpopulation of CD45 + CECs appears to have a more robust immunosuppressive property compared with their CD45 − counterparts. This was illustrated by a stronger expression of reactive oxygen species, PD-L1/PD-L2, and V-domain Ig suppressor of T-cell activation in this subpopulation. Lastly, we found a higher frequency of CECs in the blood circulation at the later cancer stage and their abundance was associated with anemia, and a poor response to immunotherapy. Finally, we report the expansion of CECs in the spleen and tumor microenvironment of mice with melanoma. We found that although CECs in tumor-bearing mice secret artemin, this was not the case for VAST-derived CECs in humans. Notably, our results imply that EPO, a frequently used drug for anemia treatment in patients with cancer, may promote the generation of CECs and subsequently abrogates the therapeutic effects of ICIs (eg, anti-PD-L1). Conclusions Our results demonstrate that anemia by the expansion of CECs may enhance cancer progression. Notably, measuring the frequency of CECs may serve as a valuable biomarker to predict immunotherapy outcomes.
Utility of p53 immunohistochemistry as a surrogate for sequencing in myeloid neoplasms: A tale of caution
Authors: Karen A. Nahmod, Koji Sasaki, Chi Young Ok, Sanam Loghavi
Journal: American Journal of Hematology (2023)

The authors declare no conflicts of interest. Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Small molecules targeting different cellular pathologies for the treatment of amyotrophic lateral sclerosis
Authors: Mohamed F. Elmansy, Cory T. Reidl, Mizzanoor Rahaman, P. Hande Özdinler, Richard B. Silverman
Journal: Medicinal Research Reviews (2023)

Abstract Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease in which the motor neuron circuitry displays progressive degeneration, affecting mostly the motor neurons in the brain and in the spinal cord. There are no effective cures, albeit three drugs, riluzole, edaravone, and AMX0035 (a combination of sodium phenylbutyrate and taurursodiol), have been approved by the Food and Drug Administration, with limited improvement in patients. There is an urgent need to build better and more effective treatment strategies for ALS. Since the disease is very heterogenous, numerous approaches have been explored, such as targeting genetic mutations, decreasing oxidative stress and excitotoxicity, enhancing mitochondrial function and protein degradation mechanisms, and inhibiting neuroinflammation. In addition, various chemical libraries or previously identified drugs have been screened for potential repurposing in the treatment of ALS. Here, we review previous drug discovery efforts targeting a variety of cellular pathologies that occur from genetic mutations that cause ALS, such as mutations in SOD1, C9orf72, FUS, and TARDP‐43 genes. These mutations result in protein aggregation, which causes neuronal degeneration. Compounds used to target cellular pathologies that stem from these mutations are discussed and comparisons among different preclinical models are presented. Because the drug discovery landscape for ALS and other motor neuron diseases is changing rapidly, we also offer recommendations for a novel, more effective, direction in ALS drug discovery that could accelerate translation of effective compounds from animals to patients.
Lipidation of a bioactive cyclotide-based CXCR4 antagonist greatly improves its pharmacokinetic profile in vivo
Authors: Dipankar Chaudhuri, Tiangong Lu, Binu Jacob, Sojan Abraham, Premlata Shankar, Michael A. Poss, Nouri Neamati, Julio A. Camarero
Journal: Journal of Controlled Release (2023)
Determinants of left ventricular filling and of the diastolic pressure-volume relation.
Authors: J C Gilbert, S A Glantz
Journal: Circulation Research (1989)

U ntil the 1970s, the left ventricle was consid- ered an isolated shell in which the left ventricular diastolic pressure-volume relation depended on the myocardium's material properties and the left ventricle's wall thickness and geometry.According to this view, the relation between diastolic pressure and volume could change only in response to chronic changes in the cardiac muscle's material properties, such as scarring due to infarction, 1 or changes in cardiac geometry due to hypertrophy.As a consequence, the diastolic pressure-volume relation was considered unique over the short term.A practical application of this assumed uniqueness was that left ventricular diastolic pressure was used as a surrogate for volume in evaluating systolic function.However, in the early 1970s, studies of patients with coronary artery disease contradicted this simplistic view of the diastolic pressure-volume relation. 2-6 In these patients, the left ventricular diastolic pressure-volume curve shifted upward temporarily immediately after cardiac pacing-induced angina and then returned to prepacing values.Later, other investigators 7 -8 observed that vasodilator and vasoconstrictor drugs, which change the vascular loading conditions of the left ventricle, also produced acute reversible shifts in the left ventricular diastolic pressure-volume curve.In the process of explaining these clinical observations, we have learned that many factors can affect left ventricular filling and the diastolic pressure-volume relation acutely.The original concept that the pressure within the left ventricle is determined by the balance between the forces due to pressures within the ventricular cavity that expand the ventricle and forces due to elasticity of the myocardium that resist this expan-
Impact of Aneuploidy and Chromosome 9p Loss on Tumor Immune Microenvironment and Immune Checkpoint Inhibitor Efficacy in NSCLC
Authors: Joao V. Alessi, Xinan Wang, Arielle Elkrief, Biagio Ricciuti, Yvonne Y. Li, Hersh Gupta, Liam F. Spurr, Hira Rizvi, Jia Luo, Federica Pecci, Giuseppe Lamberti, Gonzalo Recondo, Deepti Venkatraman, Alessandro Di Federico, Malini M. Gandhi, Victor R. Vaz, Mizuki Nishino, Lynette M. Sholl, Andrew D. Cherniack, Marc Ladanyi, Adam Price, Allison L. Richards, Mark Donoghue, James Lindsay, Bijaya Sharma, Madison M. Turner, Kathleen L. Pfaff, Kristen D. Felt, Scott J. Rodig, Xihong Lin, Matthew L. Meyerson, Bruce E. Johnson, David C. Christiani, Adam J. Schoenfeld, Mark M. Awad
Journal: Journal of Thoracic Oncology (2023)
Gastric cancer treatment: recent progress and future perspectives
Authors: Wen-Long Guan, Ye He, Rui-Hua Xu
Journal: Journal of Hematology & Oncology (2023)

Gastric cancer (GC) is one of the most common malignancies worldwide. Most patients are diagnosed at advanced stages due to the subtle symptoms of earlier disease and the low rate of regular screening. Systemic therapies for GC, including chemotherapy, targeted therapy and immunotherapy, have evolved significantly in the past few years. For resectable GC, perioperative chemotherapy has become the standard treatment. Ongoing investigations are exploring the potential benefits of targeted therapy or immunotherapy in the perioperative or adjuvant setting. For metastatic disease, there have been notable advancements in immunotherapy and biomarker-directed therapies recently. Classification based on molecular biomarkers, such as programmed cell death ligand 1 (PD-L1), microsatellite instability (MSI), and human epidermal growth factor receptor 2 (HER2), provides an opportunity to differentiate patients who may benefit from immunotherapy or targeted therapy. Molecular diagnostic techniques have facilitated the characterization of GC genetic profiles and the identification of new potential molecular targets. This review systematically summarizes the main research progress in systemic treatment for GC, discusses current individualized strategies and presents future perspectives.
Seamless phase II/III design: a useful strategy to reduce the sample size for dose optimization
Authors: Liyun Jiang, Ying Yuan
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background The traditional more-is-better dose selection paradigm, originally developed for cytotoxic chemotherapeutics, can be problematic when applied to the development of novel molecularly targeted agents. Recognizing this issue, the US Food and Drug Administration initiated Project Optimus to reform the dose optimization and selection paradigm in oncology drug development, emphasizing the need for greater attention to benefit-risk considerations. Methods We identify different types of phase II/III dose-optimization designs, classified according to trial objectives and endpoint types. Through computer simulations, we examine their operating characteristics and discuss the relevant statistical and design considerations for effective dose optimization. Results Phase II/III dose-optimization designs are capable of controlling family-wise type I error rates and achieving appropriate statistical power with substantially smaller sample sizes than the conventional approach while also reducing the number of patients who experience toxicity. Depending on the design and scenario, the sample size savings range from 16.6% to 27.3%, with a mean savings of 22.1%. Conclusions Phase II/III dose-optimization designs offer an efficient way to reduce sample sizes for dose optimization and accelerate the development of targeted agents. However, because of interim dose selection, the phase II/III dose-optimization design presents logistical and operational challenges and requires careful planning and implementation to ensure trial integrity.
Risk of estrogen receptor–specific breast cancer by family history of estrogen receptor subtypes and other cancers
Authors: Qiao-Li Wang, Yuqi Zhang, Erwei Zeng, Felix Grassmann, Wei He, Kamila Czene
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background The extent to which the risk of estrogen receptor (ER)–specific breast cancer is associated with ER status of breast cancer and other cancers among first-degree relatives is unclear. Methods This population-based cohort included 464 707 cancer-free women in Stockholm, Sweden, during 1978-2019. For ER-negative and ER-positive breast cancers, we estimated hazard ratios (HRs) associated with ER status of female first-degree relatives with breast cancer and of other cancers in all first-degree relatives. Associations between ER-negative and ER-positive status by family cancer history were estimated using logistic regression in a case-only design. Results Women with familial ER-positive breast cancer had 1.87 times (95% confidence interval [CI] = 1.77 to 1.97) higher risk of ER-positive subtype, whereas the corresponding hazard ratio for ER-negative was 2.54 (95% CI = 2.08 to 3.10) when having familial ER-negative breast cancer. The risk increased with an increasing number of female first-degree relatives having concordant subtypes and younger age at diagnosis (Ptrend &amp;lt;.001 for both). Nonbreast cancers among first-degree relatives were associated with both ER-positive (HR = 1.14, 95% CI = 1.10 to 1.17) and ER-negative (HR = 1.08, 95% CI = 1.01 to 1.16) breast cancers. Compared with women with ER-positive breast cancer, women with ER-negative breast cancer were more likely to have family history of liver (odds ratio [OR] = 1.33, 95% CI = 1.05 to 1.67), ovary (OR = 1.28, 95% CI = 1.01 to 1.61), and testicle cancer (OR = 1.79, 95% CI = 1.01 to 3.16) but less likely to have family history of endometrial cancer (OR = 0.77, 95% CI = 0.60 to 1.00) and leukemia (OR = 0.72, 95% CI = 0.56 to 0.91). Conclusions Risk of ER-specific breast cancer differs according to ER status of female first-degree relatives with breast cancer and some other cancers of first-degree relatives. This family history information should be considered in the individual risk prediction for ER subtypes.
Performance of helmet CPAP using different configurations: Turbine-driven ventilators vs Venturi devices
Authors: A. Noto, A. Cortegiani, G. Genoese, L. Appendini, C. Gregoretti, A. Carlucci, C. Crimi
Journal: Pulmonology (2023)

Traditionally, Venturi-based flow generators have been preferred over mechanical ventilators to provide continuous positive airway pressure (CPAP) through the helmet (h-CPAP). Recently, modern turbine-driven ventilators (TDVs) showed to be safe and effective in delivering h-CPAP. We aimed to compare the pressure stability during h-CPAP delivered by Venturi devices and TDVs and assess the impact of High Efficiency Particulate Air (HEPA) filters on their performance.We performed a bench study using an artificial lung simulator set in a restrictive respiratory condition, simulating two different levels of patient effort (high and low) with and without the interposition of the HEPA filter. We calculated the average of minimal (Pmin), maximal (Pmax) and mean (Pmean) airway pressure and the time product measured on the airway pressure curve (PTPinsp). We defined the pressure swing (Pswing) as Pmax - Pmin and pressure drop (Pdrop) as End Expiratory Pressure - Pmin.Pswing across CPAP levels varied widely among all the tested devices. During "low effort", no difference in Pswing and Pdrop was found between Venturi devices and TDVs; during high effort, Pswing (p<0.001) and Pdrop (p<0.001) were significantly higher in TDVs compared to Venturi devices, but the PTPinsp was lower (1.50 SD 0.54 vs 1.67 SD 0.55, p<0.001). HEPA filter addition almost doubled Pswing and PTPinsp (p<0.001) but left unaltered the differences among Venturi and TDVs systems in favor of the latter (p<0.001).TDVs performed better than Venturi systems in delivering a stable positive pressure level during h-CPAP in a bench setting.
Targeting the NLRP3 inflammasome reduces inflammation in hidradenitis suppurativa skin
Authors: Barry Moran, Conor M Smith, Alexandra Zaborowski, Mark Ryan, Jozsef Karman, Robert W Dunstan, Kathleen M Smith, Roisin Hambly, Jana Musilova, Andreea  Petrasca, Aurelie Fabre, Margaret O’Donnell, Karsten Hokamp, Kingston H G Mills, William J   Housley, Desmond C Winter, Brian Kirby, Jean M Fletcher
Journal: British Journal of Dermatology (2023)

Abstract Background Treatment for the debilitating disease hidradenitis suppurativa (HS) is inadequate in many patients. Despite an incidence of approximately 1%, HS is often under-recognized and underdiagnosed, and is associated with a high morbidity and poor quality of life. Objectives To gain a better understanding of the pathogenesis of HS, in order to design new therapeutic strategies. Methods We employed single-cell RNA sequencing to analyse gene expression in immune cells isolated from involved HS skin vs. healthy skin. Flow cytometry was used to quantify the absolute numbers of the main immune populations. The secretion of inflammatory mediators from skin explant cultures was measured using multiplex and enzyme-linked immunosorbent assays. Results Single-cell RNA sequencing analysis identified a significant enrichment in the frequency of plasma cells, T helper (Th) 17 cells and dendritic cell subsets in HS skin, and the immune transcriptome was distinct and more heterogeneous than healthy skin. Flow cytometry revealed significantly increased numbers of T cells, B cells, neutrophils, dermal macrophages and dendritic cells in HS skin. Genes and pathways associated with Th17 cells, interleukin (IL)-17, IL-1β and the NLRP3 inflammasome were enhanced in HS skin, particularly in samples with a high inflammatory load. Inflammasome constituent genes principally mapped to Langerhans cells and a subpopulation of dendritic cells. The secretome of HS skin explants contained significantly increased concentrations of inflammatory mediators, including IL-1β and IL-17A, and culture with an NLRP3 inflammasome inhibitor significantly reduced the secretion of these, as well as other, key mediators of inflammation. Conclusions These data provide a rationale for targeting the NLRP3 inflammasome in HS using small-molecule inhibitors that are currently being tested for other indications.
Postoperative adjuvant therapy for 120 patients with melanoma, including acral and mucosal subtypes: a multicentre, observational study of 2-year follow-up results
Authors: Yusuke Muto, Yumi Kambayashi, Hiroshi Kato, Satoshi Fukushima, Takamichi Ito, Takeo Maekawa, Ishizuki Shoichiro, Hiroshi Uchi, Shigeto Matsushita, Yuki  Yamamoto, Koji Yoshino, Yasuhiro  Fujisawa, Ryo Amagai, Kentaro  Ohuchi, Akira Hashimoto, Yoshihide  Asano, Taku Fujimura
Journal: British Journal of Dermatology (2023)

We retrospectively analysed 120 cases of melanoma in Japanese patients in the adjuvant setting as an observational study. Nonacral cutaneous-type melanoma (low-CSD and high-CSD types) had significantly better RFS than acral-type melanoma. On multivariate analyses, the acral subtype and agents used in adjuvant therapy were identified as important prognostic factors.
Falling-Leaf Motility of <i>Giardia lamblia</i>
Authors: Debasish Biswal, Bijay Mirdha
Journal: New England Journal of Medicine (2023)

A 24-year-old man with a kidney transplant presented with a 3-day history of diarrhea. An examination of a saline wet mount of a stool sample showed an organism moving in a “falling leaf” pattern (shown in a video).
Ensuring a Reliable Platelet Supply in the United States
Authors: William Riley, Claudia S. Cohn, Kailey Love, Jeffrey McCullough
Journal: New England Journal of Medicine (2023)

Interview with William Riley on approaches to addressing current and projected platelet shortages in the United States. (09:39)Download In the United States, a chronic shortage of platelets for transfusion is jeopardizing patient outcomes. The two technologies approved by the FDA may be inadequate for providing sufficient platelets.